A low molecular weight, selective thrombin inhibitor, inogatran, vs heparin, in unstable coronary artery disease in 1209 patients. A double-blind, randomized, dose-finding study. Thrombin inhibition in Myocardial Ischaemia (TRIM) study group.
BACKGROUND
Unstable coronary artery disease, i.e. unstable angina or non-Q wave myocardial infarction, is caused by rupture of atheromatous plaques initiating thrombus formation. Thrombin is thought to be pivotal in platelet activation and thrombus growth. The aim of the present study was to compare the effect of three different doses of a novel, low molecular weight, selective thrombin inhibitor (inogatran) with that of heparin in unstable coronary artery disease. The composite primary end-point was death, incidence of myocardial infarction, refractory angina or recurrent angina after 7 days. Secondary end-points were the same after 3 and 30 days, as were death and myocardial infarction with or without refractory angina on all three occasions.


METHODS
Patients (n = 1209) admitted with suspected unstable angina, or non-Q wave myocardial infarction, were randomly assigned to double-blind treatment with inogatran or heparin bolus doses. This was followed by a 3 day infusion with a low (LDI), medium (MDI), or high (HDI) dose of inogatran, aiming at plasma concentrations of 0.15, 0.4 or 0.8 micromol.l-1, or heparin initiated at 1200 U.h-1.


RESULTS
Treatment with inogatran resulted in median activated partial thromboplastin times after 24 h of 36, 44 and 53 s in the low, medium and high dose inogatran groups, respectively, as compared to 54 s in the heparin group (ns). At the end of the infusion, after 3 days, heparin-treated patients had fewer composite events (29.5%) than inogatran-treated patients (LDI = 39.4%, MDI = 37.6%, HDI = 36.1%; P = 0.01). The event rate after 7 days with respect to the primary end-point, however, did not differ between the groups (heparin = 41.0%, LDI = 45.7% MDI = 45.9%, HDI = 45.5%; ns). Death and myocardial infarction occurred less frequently in the heparin group (0.7%) than in the three inogatran groups (LDI = 3.6%, MDI = 2.0%, HDI = 4.0%; P < 0.05) after 3 days. After 7 days, this difference was attenuated (heparin = 2.6% vs LDI = 4.0%, MDI = 4.3%, HDI = 6.7%; P = 0.10). After 30 days there were no significant differences in event rates between the four groups. Major bleeding occurred in 1.1% of the patients within 7 days, with no differences between the groups.


CONCLUSIONS
During study drug infusion the event rate was very low in the heparin group, and none of the inogatran dosages were better than heparin in preventing ischaemic events. Furthermore, there was no relationship between event rate and inogatran dosage. Thus, this study does not indicate that the efficacy of inogatran would improve with higher doses, despite a clear dose-effect as regards the prolongation of activated partial thromboplastin time. After cessation of heparin or inogatran there was an increase in event rates, suggestive of a rebound phenomenon.
D000368:Aged; D000789:Angina, Unstable / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D000991:Antithrombins / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D006493:Heparin / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000209:etiology; D010314:Partial Thromboplastin Time; D010880:Piperidines / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D013997:Time Factors
D000991:Antithrombins; D010880:Piperidines; C099871:inogatran; D006493:Heparin; D005998:Glycine